The present invention relates to novel heterocyclic-derivatives, a method of production thereof and pharmaceutical use thereof. More particularly, the present invention relates to novel heterocyclic derivatives having an indoline ring or tetrahydroquinoline ring, a method of production thereof and pharmaceutical use thereof, specifically acyl-CoA:cholesterol acyltransferase (hereinafter ACAT) inhibitors and lipoperoxidation inhibitors.
It is a well-known fact that arteriosclerosis is an extremely important factor causing various circulatory diseases, and active studies have been undertaken in an attempt to achieve suppression of the evolution of arterial sclerosis or regression thereof. In particular, although the usefulness of a pharmaceutical agent which reduces cholesterol in blood or arterial walls has been acknowledged, an ideal pharmaceutical agent exhibiting positive clinical effects while causing less side-effects has not been realized.
In recent years, it has been clarified that cholesterol accumulated in arterial walls in the ester form thereof significantly evolves arteriosclerosis. A decrease in cholesterol level in blood leads to the reduction of accumulation of cholesterol ester in arterial walls, and is effective for the suppression of evolution of arteriosclerosis and regression thereof.
Cholesterol in food is esterified in mucous membrane of small intestine, and taken into blood as chylomicron. ACAT is known to play an important role in the generation of cholesterol ester in mucous membrane of small intestine. Thus, if esterification of cholesterol can be suppressed by inhibiting ACAT in mucous membrane of small intestine, absorption of cholesterol by mucous membrane and into blood can be presumably prevented to ultimately result in lower cholesterol level in blood.
In arterial walls, ACAT esterifies cholesterol and causes accumulation of cholesterol ester. Inhibition of ACAT in arterial walls is expected to effectively suppress accumulation of cholesterol ester.
From the foregoing, it is concluded that an ACAT inhibitor will make an effective pharmaceutical agent for hyperlipemia and arteriosclerosis, as a result of suppression of absorption of cholesterol in small intestine and accumulation of cholesterol in arterial walls.
Conventionally, for example, there have been reported, as such ACAT inhibitors, amide and urea derivatives [J. Med. Chem., 29: 1131 (1986), Japanese Patent Unexamined Publication Nos. 117651/1990, 7259/1991, 32666/1993 and 327564/1992].
However, creation and pharmacological studies of these compounds have been far from sufficient.
Meanwhile, peroxidation of low density lipoprotein (LDL) is also highly responsible for accumulation of cholesterol ester in arterial walls. In addition, it is known that peroxidation of lipids in a living body is deeply concerned with the onset of arteriosclerosis and cerebrovascular and cardiovascular ischemic diseases.
Accordingly, a compound having both ACAT inhibitory activity and lipoperoxidation inhibitory activity is highly useful as a pharmaceutical product, since it effectively reduces accumulation of cholesterol ester in arterial walls and inhibits lipoperoxidation in the living body, thereby preventing and treating various vascular diseases caused thereby.
It is therefore an object of the present invention to provide a compound having ACAT inhibitory activity and lipoperoxidation inhibitory activity, a method for production thereof and pharmaceutical use thereof, particularly as an ACAT inhibitor and lipoperoxidation inhibitor.
The present inventors have conducted intensive studies with the aim of accomplishing the above-mentioned object and found that a certain heterocyclic derivative having an indoline ring or tetrahydroquinoline ring has lipoperoxidation inhibitory activity in addition to strong ACAT inhibitory activity, and that said compound has strong anti-hyperlipemia effect and anti-arteriosclerosis effect, which resulted in the completion of the invention.
Thus, the present invention relates to a heterocyclic derivative of the formula (I) 
wherein
one of R1, R2, R3 and R4 is a group of the formula xe2x80x94NHCOxe2x80x94R6 wherein R6 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycle, optionally substituted heterocyclic alkyl, xe2x80x94RASO3A, xe2x80x94RBPO3B where RA and RB are each alkylene and A and B are each alkali metal or hydrogen atom, xe2x80x94NR7R8 where R7 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl or optionally substituted arylalkyl and R8 is hydrogen atom or lower alkyl, or xe2x80x94R9xe2x80x94OCOR10 where R9 is alkylene and R10 is optionally substituted alkyl, optionally substituted heterocycle or optionally substituted heterocyclic alkyl, and the remaining three may be the same or different and each is independently a hydrogen atom, a lower alkyl or a lower alkoxy;
R5 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heterocycle, an optionally substituted heterocyclic alkyl, an alkenyl, an alkynyl, a dialkylaminoacyloxyalkyl, xe2x80x94RDSO3D or xe2x80x94REPO3E where RD and RE are each alkylene and D and E are each alkali metal or hydrogen atom, provided that when R4 is xe2x80x94NHCOxe2x80x94R6, R5 and R6 optionally combinedly form a ring; and
m is 1 or 2,
[hereinafter this compound is also referred to as Compound (I)] and a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for producing the above-mentioned heterocyclic derivative or a pharmaceutically acceptable salt thereof, which comprises a step of
{circle around (1)} reacting an amine of the formula (II) 
wherein R11, R12 and R13 may be the same or different and each is independently hydrogen atom, lower alkyl or lower alkoxy, and R5 and m are as defined above [hereinafter also referred to as Compound (II)], and an isocyanate of the formula (III)
R7NCOxe2x80x83xe2x80x83(III) 
wherein R7 is as defined above [hereinafter also referred to as Compound (III)];
{circle around (2)} reacting Compound (II) and a halogen compound of the formula (IV)
R6xe2x80x94COXxe2x80x83xe2x80x83(IV) 
wherein X is halogen atom and R6 is as defined above [hereinafter also referred to as Compound (IV)];
{circle around (3)} reacting Compound (II) and a carboxylic acid of the formula (V)
R6xe2x80x2COOHxe2x80x83xe2x80x83(V) 
wherein R6xe2x80x2 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycle or optionally substituted heterocyclic alkyl [hereinafter also referred to as Compound (V)] or a reactive derivative thereof;
{circle around (4)} reacting an isocyanate of the formula (VI) 
wherein R5, R11, R12, R13 and m are as defined above [hereinafter also referred to as Compound (VI)], and an amine of the formula (VII)
HNR7R8xe2x80x83xe2x80x83(VII) 
wherein R7 and R8 are as defined above [hereinafter also referred to as Compound (VII)]; or
{circle around (5)} reacting a compound of the formula (VIII) 
wherein R1, R2, R3, R4 and m are as defined above [hereinafter also referred to as Compound (VIII)], and a compound of the formula (IX)
R5Xxe2x80x83xe2x80x83(IX) 
wherein R5 and X are as defined above [hereinafter also referred to as Compound (IX)].
The present invention also relates to pharmaceutical compositions, ACAT inhibitors and lipoperoxidation inhibitors containing the above-mentioned heterocyclic derivative or a pharmaceutically acceptable salt thereof.
In the present specification, each symbol denotes the following.
Lower alkyl at R1, R2, R3, R4, R8, R11, R12 and R13 may be linear or branched and preferably has 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
Lower alkoxy at R1, R2, R3, R4, R11, R12 and R13 may be linear or branched and preferably has 1 to 4 carbon atoms. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
Alkyl at R5, R6, R6xe2x80x2, R7 and R10 may be linear or branched and preferably has 1 to 12 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 1,1-dimethylpropyl, 1,1-dimethylbutyl, 1,1-dimethylpentyl, 1,1-dimethylhexyl, 3,3-dimethylbutyl, 4,4-dimethylbutyl and the like.
Cycloalkyl at R5, R6, R6xe2x80x2 and R7 preferably has 3 to 6 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
With regard to cycloalkylalkyl at R5, R6, R6xe2x80x2 and R7, its cycloalkyl moiety preferably has 3 to 6 carbon atoms and alkyl moiety preferably has 1 to 3 carbon atoms. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl and the like.
Examples of aryl at R5, R6, R6xe2x80x2 and R7 include phenyl, naphthyl and the like.
Arylalkyl at R5, R6, R6xe2x80x2 and R7 has an aryl moiety as exemplified above and its alkyl moiety preferably has 1 to 4 carbon atoms. Examples of arylalkyl include benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and the like.
Heterocycle group at R5, R6, R6xe2x80x2 and R10 is a monovalent group which occurs as a result of liberation of one hydrogen atom bonded to the ring of heterocyclic compound and may be aliphatic or aromatic. Examples thereof include pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl and the like.
Heterocyclic alkyl at R5, R6, R6xe2x80x2 and R10 has a heterocyclic moiety as exemplified above and its alkyl moiety preferably has 1 to 8 carbon atoms. Examples thereof include (1-pyrrolidinyl)butyl, morpholinopropyl, 1,1-dimethyl-2-(1-pyrrolidinyl)ethyl, 1,1-dimethyl-2-piperidinoethyl, 1,1-dimethyl-3-(imidazol-1-yl)propyl, (2,6-dimethylpiperidino)methyl, (2,6-dimethylpiperidino)ethyl, (2,6-dimethylpiperidino)propyl and the like.
The above-mentioned alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle and heterocyclic alkyl may be substituted. Examples of the substituent include alkyl, amino, hydroxy, dialkylamino, aminoalkyl, alkoxy, carboxyl, alkoxycarbonyl, carboxyalkyl, acyloxy, phenyl, phenoxy, halogen atom and the like.
Alkyl in alkyl, dialkylamino, aminoalkyl and carboxyalkyl is exemplified by the above-mentioned lower alkyl. Alkoxy in alkoxy and alkoxycarbonyl is exemplified by the above-mentioned lower alkoxy. Acyloxy may be linear or branched and preferably has 2 to 5 carbon atoms. Examples thereof include acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy and the like. Halogen atom is exemplified by those to be mentioned later. Alkyl in dialkylamino may be substituted by phenyl.
Alkenyl at R5 may be linear or branched and preferably has 2 to 8 carbon atoms. Examples thereof include ethenyl, propenyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl and the like.
Alkynyl at R5 may be linear or branched and preferably has 2 to 8 carbon atoms. Examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, 3,3-dimethyl-2-propynyl and the like.
Alkyl moiety of dialkylaminoacyloxyalkyl at R5 preferably has 1 to 8 carbon atoms, and its acyl moiety may be linear or branched and preferably has 2 to 5 carbon atoms. Examples thereof include acetyl, propionyl, butyryl, valeryl, pivaloyl and the like. The dialkylaminoacyloxyalkyl is specifically exemplified by N,N-dimethylaminoacetoxyethyl, N,N-dimethylaminoacetoxypropyl and the like.
Alkylene at RA, RB, RD, RE and R9 may be linear or branched and preferably has 1 to 8 carbon atoms. Examples thereof include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, 1,1-dimethylethylene, 2,2-dimethylpropylene and the like.
Alkali metal at A, B, D and E is preferably sodium, potassium and the like.
Halogen atom at X is exemplified by chlorine atom, bromine atom, iodine atom and the like.
When R4 xe2x80x94NHCOxe2x80x94R6, R6 and R5 may combinedly form a ring. The group (xe2x80x94R6xe2x80x94R5xe2x80x94) formed by R6 and R5 in combination may be linear or branched and preferably has 2 to 12 carbon atoms. Examples thereof include alkylene such as 1,1-dimethyltrimethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 1,1-dimethylpentamethylene, 2,2-dimethylpentamethylene and the like, and alkylene havig xe2x80x94OCOxe2x80x94 bond, such as xe2x80x94C(CH3)2CH2OCO(CH2)3xe2x80x94, xe2x80x94C(CH3)2CH2OCOC(CH3)2(CH2)3xe2x80x94 and the like.
The preferable Compound (I) of the present invention includes, for example,
1-butyl-3-(1-hexyl-4,6-dimethylindolin-5-yl)urea,
1-butyl-3-(1-hexyl-4,6-dimethylindolin-7-yl)urea,
N-(1-hexyl-4,6-dimethylindolin-5-yl)-2,2-dimethylpropanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-isobutyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylbutanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpentanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-cyclohexanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-3-ethoxypropanamide,
N-(1-ethoxypropyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-3-piperidinopropanamide,
N-(1-piperidinopropyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,
N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,6-dimethylpiperidinopropanamide, and the like, and pharmaceutically acceptable salts thereof.
The Compound (I) may be converted to a pharmaceutically acceptable salt thereof.
The Compound (I) may be converted to an acid addition salt, since it has a basic group, and the acid to form this acid addition salt includes, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like; an organic acid such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, toluenesulfonic acid and the like; and the like.
When Compound (I) has an acidic group such as carboxyl, it can form an alkali metal salt such as sodium salt, potassium salt and the like; alkaline earth metal salt such as calcium salt, magnesium salt and the like; organic base salt such as triethylamine salt, dicyclohexylamine salt, pyridine salt and the like; and the like.
The Compound (I) and pharmaceutically acceptable salts thereof can be produced, for example, by the following methods.
Production Method 1
Compound (II) and compound (III) are reacted.
This method produces a compound of the formula (I) wherein R6 is xe2x80x94NR7R8 where R8 is hydrogen atom.
This reaction generally proceeds in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate and the like may be added.
The reaction temperature is generally from xe2x88x9210xc2x0 C. to 160xc2x0 C., preferably 20-100xc2x0 C., and the reaction time is generally from 30 minutes to 10 hours.
The starting compound (II) can be prepared, for example, by the following method.
A nitro group is introduced into a compound of the general formula (X) 
wherein R11, R12, R13 and m are as defined above and R14 is an amino-protecting group [see J. Eric. Mordlander, et al., J. Org. Chem., 46, 778-782 (1981)], (introduction of nitro onto benzene ring) using nitric acid in a mixed solvent of acetic acid and sulfuric acid, and the amino-protecting group is eliminated. The compound thus obtained and compound (IX) are reacted, and nitro group is reduced using a catalyst such as palladium-carbon and the like to give starting compound (II).
Examples of the amino-protecting group at R14 include acyl such as formyl, acetyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl and the like.
Said amino-protecting group is eliminated by a method known per se. For example, it is eliminated by the action of an acid (e.g., hydrochloric acid, formic acid, trifluoroacetic acid and the like) or an alkali (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like), or other method.
Production Method 2
Compound (II) and compound (IV) are reacted.
This method produces a compound of the formula (I) wherein R6 can be any one of those defined above.
This reaction generally proceeds in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate and the like may be added.
The reaction temperature is generally from xe2x88x9210xc2x0 C. to 100xc2x0 C., preferably 0-60xc2x0 C., and the reaction time is generally from 30 minutes to 10 hours.
Production Method 3
Compound (II) and compound (V) or a reactive derivative thereof are reacted.
This method produces a compound of the formula (I) wherein R6 is R6xe2x80x2.
This reaction generally proceeds in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate and the like may be added.
The reaction temperature is generally from xe2x88x9210xc2x0 C. to 100xc2x0 C., preferably 0-60xc2x0 C., and the reaction time is generally from 30 minutes to 10 hours.
Compound (V) is subjected to said reaction as, for example, a free acid; a salt such as sodium, potassium, calcium, triethylamine, pyridine and the like; or a reactive derivative such as acid anhydride, mixed acid anhydride [e.g., substituted phosphoric acid (e.g., dialkylphosphoric acid), alkyl carbonate (e.g., monoethyl carbonate) and the like], active amide (e.g., amide with imidazole etc.), ester (e.g., cyanomethyl ester, 4-nitrophenyl ester and the like), and the like.
When Compound (V) is used as a free acid or salt in this reaction, the reaction is preferably carried out in the presence of a condensing agent. Examples of the condensing agent include dehydrating agent such as N,Nxe2x80x2-di-substituted-carbodiimides (e.g., N,Nxe2x80x2-dicyclohexylcarbodiimide), carbodiimide compounds (e.g., 1-ethyl-3-(3xe2x80x2-dimethylaminopropyl)carbodiimide, N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide and N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide), azolide compounds (e.g., N,Nxe2x80x2-carbonyldiimidazole and N,Nxe2x80x2-thionyldiimidazole) and the like. When these condensing agents are used, the reaction is considered to proceed via a reactive derivative of carboxylic acid.
Production Method 4
Compound (VI) and compound (VII) are reacted.
This method produces a compound of the formula (I) wherein R6 is xe2x80x94NR7R8.
This reaction generally proceeds in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate and the like may be added.
The reaction temperature is generally from xe2x88x9210xc2x0 C. to 160xc2x0 C., preferably 10-100xc2x0 C., and the reaction time is generally from 30 minutes to 10 hours.
The starting compound (VI) can be produced, for example, by dissolving compound (II) in an inert solvent and bubbling in phosgene.
Production Method 5
Compound (VIII) and compound (IX) are reacted.
This reaction generally proceeds in an inert solvent. Examples of the inert solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, water and the like, and mixtures thereof.
In addition, a base such as triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydride and the like may be added.
The reaction temperature is generally from xe2x88x9210xc2x0 C. to 100xc2x0 C., preferably 0-60xc2x0 C., and the reaction time is generally from 30 minutes to 10 hours.
The starting compound (VIII) can be prepared, for example, by the method wherein a nitro group is introduced into a compound of the formula (X) (introduction of nitro onto benzene ring), and the nitro group is reduced using a catalyst such as palladium-carbon and the like to give a compound of the formula (XI) 
wherein R11, R12, R13, R14 and m are as defined above. Using this compound as a starting compound and according to Production Method 2, a compound of the formula (XII) 
wherein R1, R2, R3, R4, R14 and m are as defined above, is obtained. This compound is deprotected to give compound (VIII).
The Compound (I) of the present invention obtained as in the above can be purified by a method conventionally known, such as chromatography and recrystallization.
This Compound (I) can be converted to a pharmaceutically acceptable salt by a method known per se.
The Compound (I) and pharmaceutically acceptable salts thereof of the present invention show superior ACAT inhibitory activity and lipoperoxidation inhibitory activity in mammals (e.g., human, cow, horse, dog, cat, rabbit, rat, mouse, hamster and the like) and are useful as ACAT inhibitors and hyperlipemia inhibitors. To be specific, they are useful for the prevention and treatment of arteriosclerotic lesions such as arteriosclerosis, hyperlipemia and diabetes, as well as ischemic diseases of brain, heart and the like.
A pharmaceutical composition containing Compound (I) or a pharmaceutically acceptable salt thereof of the present invention may contain an additive. Examples of the additive include excipients (e.g., starch, lactose, sugar, calcium carbonate and calcium phosphate), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose and crystalline cellulose), lubricants (e.g., magnesium stearate and talc), disintegrators (e.g., calcium carboxymethylcellulose and talc), and the like.
The above-mentioned ingredients are mixed, and the mixture can be formulated into an oral preparation such as capsule, tablet, fine granules, granules, dry syrup and the like, or a parenteral preparation such as injection, suppository and the like by a method conventionally known.
While the dose of Compound (I) and pharmaceutically acceptable salts thereof of the present invention varies depending on administration target, symptom and other factors, it is generally about 0.1-50 mg/kg body weight per dose for an adult patient with hypercholesterolemia by oral administration in about one to three times a day.
The present invention is described in more detail in the following by way of Examples, to which the present invention is not limited.